Geographical Variation in Social Determinants of Female Breast Cancer Mortality Across US Counties.

Importance: Breast cancer mortality is complex and traditional approaches that seek to identify determinants of mortality assume that their effects on mortality are stationary across geographic space and scales. Objective: To identify geographic variation in the associations of population demographics, environmental, lifestyle, and health care access with breast cancer mortality at the US county-level. Design, Setting, and Participants: This geospatial cross-sectional study used data from the Surveillance, Epidemiology, and End Results (SEER) database on adult female patients with breast cancer. Statistical and spatial analysis was completed using adjusted mortality rates from 2015 to 2019 for 2176 counties in the US. Data were analyzed July 2022. Exposures: County-level population demographics, environmental, lifestyle, and health care access variables were obtained from open data sources. Main Outcomes and Measures: Model coefficients describing the association between 18 variables and age-adjusted breast cancer mortality rate. Compared with a multivariable linear regression (OLS), multiscale geographically weighted regression (MGWR) relaxed the assumption of spatial stationarity and allowed for the magnitude, direction, and significance of coefficients to change across geographic space. Results: Both OLS and MGWR models agreed that county-level age-adjusted breast cancer mortality rates were significantly positively associated with obesity (OLS: ß, 1.21; 95% CI, 0.88 to 1.54; mean [SD] MGWR: ß, 0.72 [0.02]) and negatively associated with proportion of adults screened via mammograms (OLS: ß, -1.27; 95% CI, -1.70 to -0.84; mean [SD] MGWR: ß, -1.07 [0.16]). Furthermore, the MGWR model revealed that these 2 determinants were associated with a stationary effect on mortality across the US. However, the MGWR model provided important insights on other county-level factors differentially associated with breast cancer mortality across the US. Both models agreed that smoking (OLS: ß, -0.65; 95% CI, -0.98 to -0.32; mean [SD] MGWR: ß, -0.75 [0.92]), food environment index (OLS: ß, -1.35; 95% CI, -1.72 to -0.98; mean [SD] MGWR: ß, -1.69 [0.70]), exercise opportunities (OLS: ß, -0.56; 95% CI, -0.91 to -0.21; mean [SD] MGWR: ß, -0.59 [0.81]), racial segregation (OLS: ß, -0.60; 95% CI, -0.89 to -0.31; mean [SD] MGWR: ß, -0.47 [0.41]), mental health care physician ratio (OLS: ß, -0.93; 95% CI, -1.44 to -0.42; mean [SD] MGWR: ß, -0.48 [0.92]), and primary care physician ratio (OLS: ß, -1.46; 95% CI, -2.13 to -0.79; mean [SD] MGWR: ß, -1.06 [0.57]) were negatively associated with breast cancer mortality, and that light pollution was positively associated (OLS: ß, 0.48; 95% CI, 0.24 to 0.72; mean [SD] MGWR: ß, 0.27 [0.04]). But in the MGWR model, the magnitude of effect sizes and significance varied across geographical regions. Inversely, the OLS model found that disability was not a significant variable for breast cancer mortality, yet the MGWR model found that it was significantly positively associated in some geographical locations. Conclusions and Relevance: This cross-sectional study found that not all social determinants associated with breast cancer mortality are spatially stationary and provides spatially explicit insights for public health practitioners to guide geographically targeted interventions.

Barriers and facilitators to effective cervical cancer screening in Belize: a qualitative analysis.

PURPOSE: Belize has among the highest cervical cancer incidence and mortality rates of Latin American and Caribbean countries. This study evaluates the perspectives of key stakeholders for cervical cancer screening in Belize and identifies the barriers and facilitators for providing equitable access to prevention services. METHODS: Semi-structured interviews discussing cervical cancer screening were conducted with key stakeholders across the six districts of Belize in 2018. Interviews were transcribed, coded, and analyzed thematically; themes were organized by levels of the social-ecological model. RESULTS: We conducted 47 interviews with health care providers (45%), administrators (17%), government officials (25%), and other stakeholders (13%). Majority (78%) of interviews were from the public sector. Perceived barriers to cervical cancer screening were identified across multiple levels: (1) Individual Patient: potential delays in Pap smear results and fear of a cancer diagnosis; (2) Provider: competing clinician responsibilities; (3) Organizational: insufficient space and training; (4) Community: reduced accessibility in rural areas; and (5) Policy: equipment and staffing budget limitations. The main facilitators we identified included the following: (1) at the Community level: resource-sharing between public and private sectors and dedicated rural outreach personnel; (2) at the Policy level: free public screening services and the establishment of population-based screening. CONCLUSION: Despite free, publicly available cervical cancer screening in Belize, complex barriers affect access and completion of management when abnormal screening tests are identified. Provider workload, education outreach, and additional funding for training and facilities are potential areas for strengthening this program and increasing detection and management for cervical cancer control.

Sonodynamic Therapy for the Treatment of Glioblastoma Multiforme in a Mouse Model Using a Portable Benchtop Focused Ultrasound System.

Sonodynamic therapy (SDT) is an application of focused ultrasound (FUS) that enables a sonosensitizing agent to prime tumors for increased sensitivity during sonication. Unfortunately, current clinical treatments for glioblastoma (GBM) are lacking, leading to low long-term survival rates among patients. SDT is a promising method for treating GBM in an effective, noninvasive, and tumor-specific manner. Sonosensitizers preferentially enter tumor cells compared to the surrounding brain parenchyma. The application of FUS in the presence of a sonosensitizing agent generates reactive oxidative species resulting in apoptosis. Although this therapy has been shown previously to be effective in preclinical studies, there is a lack of established standardized parameters. Standardized methods are necessary to optimize this therapeutic strategy for preclinical and clinical use. In this paper, we detail the protocol to perform SDT in a preclinical GBM rodent model using magnetic resonance-guided FUS (MRgFUS). MRgFUS is an important feature of this protocol, as it allows for specific targeting of a brain tumor without the need for invasive surgeries (e.g., craniotomy). The benchtop device used here can focus on a specific location in three dimensions by clicking on a target on an MRI image, making target selection a straightforward process. This protocol will provide researchers with a standardized preclinical method for MRgFUS SDT, with the added flexibility to change and optimize parameters for translational research.

Explainable Machine Learning to Bring Database to the Bedside: Development and Validation of the TROUT (Trauma fRailty OUTcomes) Index, a Point-of-Care Tool to Prognosticate Outcomes After Traumatic Injury Based on Frailty.

OBJECTIVE: Exemplify an explainable machine learning framework to bring database to the bedside; develop and validate a point-of-care frailty assessment tool to prognosticate outcomes after injury. BACKGROUND: A geriatric trauma frailty index that captures only baseline conditions, is readily-implementable, and validated nationwide remains underexplored. We hypothesized Trauma fRailty OUTcomes (TROUT) Index could prognosticate major adverse outcomes with minimal implementation barriers. METHODS: We developed TROUT index according to Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis guidelines. Using nationwide US admission encounters of patients aged ≥65 years (2016-2017; 10% development, 90% validation cohorts), unsupervised and supervised machine learning algorithms identified baseline conditions that contribute most to adverse outcomes. These conditions were aggregated into TROUT Index scores (0-100) that delineate 3 frailty risk strata. After associative [between frailty risk strata and outcomes, adjusted for age, sex, and injury severity (as effect modifier)] and calibration analysis, we designed a mobile application to facilitate point-of-care implementation. RESULTS: Our study population comprised 1.6 million survey-weighted admission encounters. Fourteen baseline conditions and 1 mechanism of injury constituted the TROUT Index. Among the validation cohort, increasing frailty risk (low=reference group, moderate, high) was associated with stepwise increased adjusted odds of mortality {odds ratio [OR] [95% confidence interval (CI)]: 2.6 [2.4-2.8], 4.3 [4.0-4.7]}, prolonged hospitalization [OR (95% CI)]: 1.4 (1.4-1.5), 1.8 (1.8-1.9)], disposition to a facility [OR (95% CI): 1.49 (1.4-1.5), 1.8 (1.7-1.8)], and mechanical ventilation [OR (95% CI): 2.3 (1.9-2.7), 3.6 (3.0-4.5)]. Calibration analysis found positive correlations between higher TROUT Index scores and all adverse outcomes. We built a mobile application ("TROUT Index") and shared code publicly. CONCLUSION: The TROUT Index is an interpretable, point-of-care tool to quantify and integrate frailty within clinical decision-making among injured patients. The TROUT Index is not a stand-alone tool to predict outcomes after injury; our tool should be considered in conjunction with injury pattern, clinical management, and within institution-specific workflows. A practical mobile application and publicly available code can facilitate future implementation and external validation studies.

Improving sexually transmitted infection screening, testing, and treatment among people with HIV: A mixed method needs assessment to inform a multi-site, multi-level intervention and evaluation plan.

Bacterial sexually transmitted infections (STIs) continue to be a worsening public health concern in the United States (US). Though the national incidence of HIV infection has decreased over recent years, that of chlamydia, gonorrhea, and syphilis have not. Despite national recommendations on prevention, screening, and treatment of these STIs, these practices have not been standardized. Nine Health Resources and Services Administration Ryan White HIV/AIDS Program funded clinics across 3 US jurisdictions (Florida, Louisiana, and Washington, DC), were selected as clinical demonstration sites to be evaluated in this mixed method needs assessment to inform a multi-site, multi-level intervention to evaluate evidence-based interventions to improve STI screening and testing of bacterial STIs among people with or at risk for HIV. These 3 US jurisdictions were selected due to having higher than national average incidence rates of HIV and bacterial STIs. Descriptive statistics and deductive analysis were used to assess quantitative and qualitative needs assessment data. Results indicate the following needs across participating sites: inconsistent and irregular comprehensive sexual behavior history taking within and among sites, limited routine bacterial STI testing (once/year and if symptomatic) not in accordance with CDC recommendations, limited extragenital site gonorrhea/chlamydia testing, limited annual training on STI-related topics including LGBTQ health and adolescent/young adult sexual health, and limited efforts for making high-STI incidence individuals feel welcome in the clinic (primarily LGBTQ individuals and adolescents/young adults). These findings were used to identify interventions to be used to increase routine screenings and testing for bacterial STIs.

Assessment of Cervical Cancer Prevention and Treatment Infrastructure in Belize.

PURPOSE: Belize has one of the highest cervical cancer burdens among Latin American and Caribbean countries, despite the implementation of national policies to increase access to prevention and treatment services. This study evaluates the policies, infrastructure, and workforce of the cervical cancer management system in Belize to inform capacity building efforts. METHODS: In 2018, health facility assessments were conducted across all six districts of Belize at the national pathology facility and 12 public facilities identified as critical to cervical cancer control. Human and infrastructure resource availability and existing policies related to cervical cancer screening and treatment services were assessed through a structured instrument. RESULTS: The public cervical cancer screening workforce in Belize consists of 75 primary care nurses and physicians-one per 1,076 screening-eligible women, with 44% conducting rural outreach. All districts have at least one screening facility, but 50% perform screening services only once per week. Colposcopy and loop electrical excision procedures are available in three and four districts, respectively; radical hysterectomy and chemotherapy are available in two districts; and radiation therapy is unavailable. Of essential pathology equipment, 38.5% were present and functional, 23% were present but nonfunctional, and 38.5% were unavailable. Additionally, 35% of supplies were unavailable at the time of assessment, and 75% were unavailable at least once in the 12 months before assessment. CONCLUSION: Public-sector cervical cancer management services differ among districts of Belize, with tertiary service availability concentrated in the largest district. Screening, outreach, and pathology are limited mostly by resource availability. This study characterizes the current capacity of services in Belize and pinpoints health system components for future investment and capacity-building efforts.

Downregulation of CD40L-CD40 attenuates seizure susceptibility and severity of seizures.

Unregulated neuro-inflammation mediates seizures in temporal lobe epilepsy (TLE). Our aim was to determine the effect of CD40-CD40L activation in experimental seizures. CD40 deficient mice (CD40KO) and control mice (wild type, WT) received pentenyltetrazole (PTZ) or pilocarpine to evaluate seizures and status epilepticus (SE) respectively. In mice, anti-CD40L antibody was administered intranasally before PTZ. Brain samples from human TLE and post-seizure mice were processed to determine CD40-CD40L expression using histological and molecular techniques. CD40 expression was higher in hippocampus from human TLE and in cortical neurons and hippocampal neural terminals after experimental seizures. CD40-CD40L levels increased after seizures in the hippocampus and in the cortex. After SE, CD40L/CD40 levels increased in cortex and showed an upward trend in the hippocampus. CD40KO mice demonstrated reduction in seizure severity and in latency compared to WT mice. Anti-CD40L antibody limited seizure susceptibility and seizure severity. CD40L-CD40 interaction can serve as a target for an immuno-therapy for TLE.

Blood-based biomarkers for prediction of intracranial hemorrhage and outcome in patients with moderate or severe traumatic brain injury.

BACKGROUND: Early identification of traumatic intracranial hemorrhage (ICH) has implications for triage and intervention. Blood-based biomarkers were recently approved by the Food and Drug Administration (FDA) for prediction of ICH in patients with mild traumatic brain injury (TBI). We sought to determine if biomarkers measured early after injury improve prediction of mortality and clinical/radiologic outcomes compared with Glasgow Coma Scale (GCS) alone in patients with moderate or severe TBI (MS-TBI). METHODS: We measured glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) on arrival to the emergency department (ED) in patients with blunt TBI enrolled in the placebo arm of the Prehospital TXA for TBI Trial (prehospital GCS score, 3-12; SPB, > 90). Biomarkers were modeled individually and together with prehospital predictor variables [PH] (GCS score, age, sex). Data were divided into a training data set and test data set for model derivation and evaluation. Models were evaluated for prediction of ICH, mass lesion, 48-hour and 28-day mortality, and 6-month Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). Area under the curve (AUC) was evaluated in test data for PH alone, PH + individual biomarkers, and PH + three biomarkers. RESULTS: Of 243 patients with baseline samples (obtained a median of 84 minutes after injury), prehospital GCS score was 8 (interquartile range, 5-10), 55% had ICH, and 48-hour and 28-day mortality were 7% and 13%, respectively. Poor neurologic outcome at 6 months was observed in 34% based on GOS-E of 4 or less, and 24% based on DRS greater than or equal to7. Addition of each biomarker to PH improved AUC in the majority of predictive models. GFAP+PH compared with PH alone significantly improved AUC in all models (ICH, 0.82 vs. 0.64; 48-hour mortality, 0.84 vs. 0.71; 28-day mortality, 0.84 vs. 0.66; GOS-E, 0.78 vs. 0.69; DRS, 0.84 vs. 0.81, all p < 0.001). CONCLUSION: Circulating blood-based biomarkers may improve prediction of neurological outcomes and mortality in patients with MS-TBI over prehospital characteristics alone. Glial fibrillary acidic protein appears to be the most promising. Future evaluation in the prehospital setting is warranted. LEVEL OF EVIDENCE: Prospective, Prognostic and Epidemiological, level II.

Educational Case: Wilms Tumor (Nephroblastoma).

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Efficacy of Medical Student Surgery Journal Club.

BACKGROUND: Journal clubs exist in a variety of forms in medical schools across the United States. Many incorporate a full spectrum of medical specialties, some are specific to certain interest groups or specialties, and many widely vary in whether or not they are school mandated or student-run. While these clubs are ubiquitously scattered throughout medical education, there has been very little quantitative or qualitative analysis regarding the efficacy of these clubs in enhancing medical students' abilities to evaluate clinical literature. The purpose of this study was to evaluate the effects of attending Surgical Journal Club meetings at Eastern Virginia Medical School from both a qualitative and quantitative perspective. The authors' hypothesis was that regular attendance of these sessions would improve student performance from a multitude of perspectives and demonstrate the value of clinical literature analysis earlier in medical education. METHODS: A fifteen question Likert survey was administered on an optional basis to thirty-six medical students attending journal club. Responses were analyzed anonymously, and there was no incentive or demerit for completing the survey. Data was compiled and the mean, median, and mode for each question calculated with "5" corresponding to "Strongly Agree" and "1" corresponding to "Strongly Disagree." RESULTS: Twenty-seven of thirty-six attendees to our seventh journal club meeting completed the survey. Student responses were overwhelming positive, with all but one question reaching above "Agree" by analysis of the mean responses. CONCLUSION: Journal clubs remain an integral part of medical education but their importance has been diminished in recent years due to the increasing demands of other aspects of the first two years in medical school. We described a medical student run/established journal club that increased students' interest in surgery, their perceived knowledge-base, and comfort in critically analyzing medical journal articles.

The procoagulant molecule plasminogen activator inhibitor-1 is associated with injury severity and shock in patients with and without traumatic brain injury.

BACKGROUND: Traumatic injury is associated with an increased risk of coagulopathy and venous thrombosis. plasminogen activator inhibitor-1 (PAI-1) is a procoagulant molecule that inhibits tPA/uPA, thrombomodulin, and activated protein C. We hypothesized that elevated PAI-1 levels would be associated with increased Injury Severity Score (ISS) in injured patients with and without traumatic brain injury and that PAI-1 levels would vary with injury type. METHODS: We retrospectively analyzed demographic, ISS, and hemodynamic data from a prospectively collected database. Patients with traumatic injury requiring intensive care unit admission (n = 268) were classified as multiple injuries, isolated body, or isolated head based on Abbreviated Injury Severity score. Admission PAI-1 levels were quantified using a Luminex analyte platform. Univariate tests for association informed the construction of a multivariate model of the relationship between PAI-1 and ISS. RESULTS: Plasminogen activator inhibitor-1 positively associated with ISS (p < 0.0001) and was highest in patients with ISS greater than 35 (p < 0.0001). Plasminogen activator inhibitor-1 was significantly different between multiple injuries, isolated body, and isolated head patients (p < 0.0001). On univariate analysis, age (p = 0.0011), hypotension (p = 0.0076), and alcohol intoxication (p = 0.0024) were all positively associated with PAI-1 level. Admission international normalized ratio was not associated with PAI-1 level (p = 0.638). After adjusting for age, sex, hypotension, and alcohol intoxication, higher PAI-1 levels were associated with higher ISS (p < 0.0001). CONCLUSION: Elevated PAI-1 at admission is associated with higher ISS. This association is more pronounced in patients with hypotension. These findings suggest that PAI-1 levels may reflect the burden of endothelial damage and platelet activation after injury. LEVEL OF EVIDENCE: Prognostic, level III.